CFTR Modulators Counteract F508del CFTR Functional Defects in a Pancreatic Epithelial Model of Cystic Fibrosis

Area of Science:

• Cell Biology
• Epithelial Physiology
• Pharmacology

Background:

• Cystic fibrosis (CF) is a genetic disorder caused by CFTR gene mutations, affecting multiple organs.
• CFTR modulators are effective in airway epithelia, but their impact on pancreatic CF epithelia is less understood.

Purpose of the Study:

• To investigate the efficacy of CFTR modulators (ivacaftor, tezacaftor, elexacaftor) in restoring pancreatic ductal epithelial function in cystic fibrosis.
• To assess modulator effects under pro-inflammatory conditions induced by lipopolysaccharide (LPS).

Main Methods:

• CFPAC-1 cells (F508del CFTR mutation) were cultured and treated with individual or combined CFTR modulators.
• Functional parameters assessed included transepithelial electrical conductance, fluid reabsorption, apical pH, protein concentration, and microviscosity.
• Cells were preconditioned with LPS to simulate inflammation.

Main Results:

• Tezacaftor and elexacaftor, particularly in triple combination, significantly improved epithelial function.
• LPS increased pro-inflammatory cytokines (IL6, IL-8, IL-1β) and apical fluid protein content.
• CFTR modulators maintained or enhanced ion/fluid transport restoration despite LPS stimulus, but did not reduce cytokine levels.

Conclusions:

• CFTR modulators can restore key physiological functions in cystic fibrosis pancreatic epithelia in vitro.
• Modulator efficacy persists under pro-inflammatory stress, suggesting therapeutic potential beyond lung disease.